This is a treatment development research proposal. The ultimate goal of the planned research is to develop an effective combined cognitive therapy (CT) + drug treatment for patients with drug resistant depression (DRD) (i.e., depression that is refractory to medication). The present proposal has three main aims: (a) Develop a treatment manual for CT + drug treatment for DRD that integrates three existing forms of CT (CT for depression [A. Beck et al., 1979], CT for personality disorders [A. Beck et al., 1990; Layden et al., 1993], and CT for anxiety disorders [A. Beck & Emery, 1985; A. Beck et al., 1992]), and that specifies interventions for combining CT and medication when two therapists (psychotherapist and pharmacotherapist) provide the treatment; (b) obtain outpatient randomized control pilot data on the clinical value of the CT + drug treatment, using the standard antidepressant desipramine (DMI), to obtain effect sizes and to determine if the treatment merits further investigation in a clinical trial; and (c) develop a therapist adherence measure for the combined treatment. Secondary aims are to: (a) evaluate and further develop a method to reliably identify DRD, and (b) develop a measure to assess DRD patients beliefs about medication, psychotherapy, causes of depression, and necessary factors for its cure that might affect treatment acceptability and compliance with pharmacological and psychotherapeutic regimens. To accomplish the foregoing aims, 30 patients will be entered into two treatments: CT + DMI (n = 18) and DMI + Clinical Management (n = 12). The first 6 of the 18 CT + DMI patients will be treated in a pre-pilot phase before randomization begins. All treatments will continue for 6 months. The major assessment battery will be administered at intake, 3 months, 6 months, and 6 month follow-up. All treatments will be closely monitored via audiotapes and supervision for purposes of development of the CT + drug treatment. The audiotapes also will be used for development of the adherence measure. The primary outcome measures will be % attrition, % remitted, Hamilton Rating Scale for Depression scores, and Beck Depression Inventory scores. Compliance with the treatment regimens also will be a targeted and measured outcome variable.